"Kill the king, yeah, strike him down."

"Kill the king, yeah
Strike him down

Power, power it happens every day
Power, devour all along the way
Oh no, move me out of harm
I need a spell and a charm
And fly like the wind
I'm no pawn, so be gone, speed on and on
Kill the king

Treason, treason, the specter looms again
Treason, reason, the realm is safe and then
Oh no, move away from harm
I need a spell and a charm
Fly like the rainbow
I'm no pawn, so be gone, speed on and on

Kill the king
Tear him down
Kill the king, yeah
Got to take his crown
Crown

Kill the king
He'll rule no more
Strike him dead
The people roar"

From Rainbow's Kill the King (yes, Ritchie Blackmore and Ronnie James Dio)

I’ve now had time to view “The Purple Wedding” episode of Game of Thrones and I thought I‘d throw in my one and a half cents regarding the ever-hated King Joffrey’s death. So, what killed Joffrey? There have been some very good pieces around the web discussing the matter. On Boing Boing, Rachel Nuwer mentioned cyanide as a possibility. So did Deborah Blum (by the way, read The Poisoner’s Handbook if you haven’t yet, it’s great). Dr. Raychelle Burks has pointed towards strychnine. The Nature’s Poisons blog has implicated nicotine.

So, what do I think?

All of the above are great thoughts. And of course, we are talking about a fictional series of books on which the television series is based, so there is pretty much no right answer here, so let’s speculate. I love that word. I don't get to speculate much in the normal work hours.

I think Nature’s Poisons is definitely on the right track in his assessment of the poisoning. We should be looking at something that affects the parasympathetic nervous system (PSNS). Primarily, we should be looking at some drug that activates the PSNS, i.e. a receptor agonist of some sort. The PSNS’s main neurotransmitter is acetylcholine (but it’s not the only one). Acetylcholine acts on two basic receptors, muscarinic acetylcholine receptors (mAChRs) and nicotinic acetylcholine receptors (nAChRs). Nature’s poisons focuses on nicotine as the culprit and its agonist behavior at the nAChRs. So, let’s focus on the mAChRs.

The different types of mAChRs are located in various parts of the body including the heart, blood vessels, smooth muscles, liver, lungs, salivary glands, sweat glands, bladder, and brain. As with the nAChRs, the acronym SLUDGEM is in play.

Salivation stimulation

Lacrimal stimulation

Urination

Defecation

Gastrointestinal upset

Emesis

Miosis

 

Other adverse effects include:

 

Bronchial secretions

Bronchioconstriction

Constriction of the pharynx

Bradycardia

Hypotension

Hypothermia

Vasodilation

Tremors

Convulsions

Well, know that we know possible adverse effects, what drugs affect mAChRs? There are a few, but what "plant"-based drugs are known to be mAChRs agonists? Afterall, in the novel, "The Strangler" is plant-derived and is made from the "leaves".

 

 

Let’s entertain mushrooms for a few moments. While not necessarily a "plant" (Kingdom Plantae), fungi were historically classified as plants until not long ago (or so I'd like to think as the Fungi kingdom is as old as I am) and may still be mistakenly classified as so. We aren't referring to psychoactive mushrooms of the Psilocybe kind, also known as magic mushrooms or ‘shrooms. I’m referring to poisonous mushrooms. Mushrooms that are potentially deadly. Some species of fungi (Clitocybes or Inocybes) contain an alkaloid called muscarine. Pharmacologically, muscarine functions as an agonist of the mChRs.

 

With medical intervention (use of atropine as an antidote), death from muscarine mushroom intoxication is extremely rare. Without intervention, death may occur, but it is still relatively rare. Of course, as we like to say in forensic toxicology, the dose makes the poison. But in Westeros, anything is possible. In a suitable dosage, muscarine could do the job.

Now, let us consider the possible use of pilocarpine, the alkaloid found in the genus Pilocarpus. A common name for many species of this genus is Jaborandi. These shrubs/plants can be found growing in South America. Similar to muscarine, pilocarpine is a mAChR agonist. It is considered an essential medicine according to the World Health Organization and is commonly used to treat glaucoma and xerostoma (dry mouth) and in the process of diagnosing cystic fibrosis. But as an agonist at mAChR, the same adverse effects presented above are possible.

Acute poisonings with pilocarpine have occurred, but with medical intervention (atropine again!), the patients survived and recovered. Deaths have occured as well. Again, in the appropriate dosages, pilocarpine can cause death.
 

Let’s recall the death scene from the television show.

Joffrey drinks wine and eats pie.

Joffrey mentions that the pie is dry and needs a drink.

Joffrey begins to cough and acts as if he is choking and gasps for air.

                Possible bronchioconstriction or constriction of pharynx leading to dyspnea

Joffrey falls to the ground and vomits.

                Possible increased salivation and eventual emesis

Joffrey exhibits some shakiness.

                Maybe some small tremors.

Joffrey’s pupils are constricted

                Miosis is present.

Joffrey still cannot breathe and his face is blue colored.

                Asphyxia leading to acute cyanosis.

The symptoms of muscarine or pilocarpine intoxication and the observed effects during the death scene line up pretty well.

Cyanide, strychnine, nicotine, and now muscarine and pilocarpine. What do you think? What lead to King Joffrey’s death?





References

Ishii, M. and Kurachi Y. (2006) Muscarinic acetylcholine receptors. Curr Pharm Des. 12: 3573-3581.

Flomenbaum, N.E., Goldfrank, L.R., Hoffman, R.S. et al. (2006) Goldfrank's Toxicologic Emergencies, 8th Edition. Chapter 113: Mushrooms. 1564-1576

Lurie, Y., Wasser S.P., Taha M. et al. (2009) Mushroom poisoning from species of genus Inocybe (fiber head mushroom): a case series with exact species identification. Clin Toxicol (Phila). 47: 562-565.

Baselt, R.C. (2011) Disposition of Toxic Drugs and Chemicals in Man, 9th Edition. Biomedical Publications. Seal Beach, CA.

Flomenbaum, N.E., Goldfrank, L.R., Hoffman, R.S. et al. (2006) Goldfrank's Toxicologic Emergencies, 8th Edition. Chapter 114: Plants. 1577-1602.

Image of King Joffrey from HBO's Game of Thrones television series can be found via ABC News here.

Image of of Inocybe geophylla mushroom by Patrick Poitras (2009) can be found here.

Image of Pilocarpus can be found here at HealthyHomeGardening.com.